The Cytokine Storm in COVID-19: The Strongest Link to Morbidity and Mortality in the Current Epidemic
Round 1
Reviewer 1 Report
This "narrative" review aims to emphasize the importance of the cytokine storm situation and the dangers behind it, especially in critically ill patients and immunodeficient patients.
The novelty degree is poor, for a thematic largely treated in literature. For example, inserting the following keywords "cytokine storm" and "COVID-19" in the Scopus database, to date, 5,056 documents have been published.
In order to improve the manuscript, I suggest treating this thematic focusing on the new variants of the SARS-CoV-2 and their effects on the cytokine storm. I believe that the paper should treat these arguments, increasing its novelty degree. Please, revisit the review inserting new paragraphs about the delta variant and the relative symptoms, the omicron variant, the effects of the virus in fully vaccinated subjects.
At this stage of the pandemic, these are the thematic that could be of interest to the readers.
Author Response
We would like to thank the reviewer for the constructive comments that have helped us in improving this article in a scientific way.
-In the new version of the review, we discussed the cytokine storm as dangerous phase in this epidemic and a correlation was done with the new variants of the SARS-CoV-2 and their effects on the cytokine storm. New paragraphs about the delta variant and the relative symptoms, the omicron variant and its clinical effects was added. Lines: 298-323.
Reviewer 2 Report
Cytokines alone do not reflect morbidity and mortality. Alarmins like calprotectin are important indicators.
The discussion should be revised to include the fact that COVID antibodies do not seem to be effective against omicron.
Important references shou be included and discussed
Conti P, Ronconi G, Caraffa A, Gallenga CE, Ross R, Frydas I, Kritas SK. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies. J Biol Regul Homeost Agents. 2020 March-April,;34(2):327-331. doi: 10.23812/CONTI-E. PMID: 32171193.
Theoharides TC. COVID-19, pulmonary mast cells, cytokine storms, and beneficial actions of luteolin. Biofactors. 2020 May;46(3):306-308. doi: 10.1002/biof.1633. Epub 2020 Apr 27. PMID: 32339387; PMCID: PMC7267424.
Theoharides TC. Could SARS-CoV-2 Spike Protein Be Responsible for Long-COVID Syndrome? Mol Neurobiol. 2022 Jan 13:1–12. doi: 10.1007/s12035-021-02696-0. Epub ahead of print. PMID: 35028901; PMCID: PMC8757925.
Author Response
We would like to thank the reviewer for the constructive comments that have helped us to improve this article in a scientific way.
In the new version of the review, we discuss the cytokine storm as dangerous phase in this epidemic and a correlation was done with the new variants of the SARS-CoV-2 and their effects on the cytokine storm. New paragraphs about the delta variant and the relative symptoms, the omicron variant and the effects of the virus was added. Lines: 298-323
The specific references were discussed wildly as discussed below.
***Interleukin (IL)-1β and IL-6 mediators of lung inflammation, fever and fibrosis. Suppression of pro-inflammatory IL-1 family members and IL-6 have been shown to have a therapeutic effect in many inflammatory diseases, including viral infections. Lines: 215-218, ref. (69).
***A recent report correlated coronaviruses infection with activation of mast cells and subsequent cytokine storms in the lungs was added. Lines: 271-280; ref. 97.
***SARS-CoV-2 infects cells via its spike protein binding to its surface receptor on target cells and results in acute symptoms involving especially the lungs known as COVID-19. Lines: 337-344, ref 102.
Reviewer 3 Report
The paper is interesting and well written. However, it is useful to improve the discussion on cytokine storm considering and adding as references paper by Murdaca et al concerning this topic. I suggest to discuss the role of vitamin D and microbioma in supporting immune system (see and add as references papers by Murdaca et al concerning these topics). Finally, a briefly note of COVID19 in patients with autoimmune diseases is needed (see and add as references papers by Ferri et al concerning this topic)
Author Response
We would like to thank the reviewer for the constructive comments that have helped us improve this article in a scientific way.
Changes were done as the reviewer ordered. The role of vitamin D and microbiome in supporting immune system were discussed in lines: 353-363; ref. 104. Autoimmune diseases and COVID-19 were discussed in lines: 193-196, ref. 66.
Round 2
Reviewer 1 Report
Following the reviewers' suggestions, the authors have improved their manuscript. Nevertheless, several changes are required, particularly in the introduction section. The authors missed introducing the mutated scenario about the COVID-19, after the massive vaccination campaign that, combined with the new virus variants, has reduced the mortality rate of the COVID-19. This is a crucial point.
Moreover, it could be of interest a new paragraph about the effect of the vaccination on the cytokine storm.
These suggestions may improve the novelty degree of the manuscript.
Author Response
We would to thank the reviewer again for his constructive comments. The comments are discussed as described below.
- The authors missed introducing the mutated scenario about the COVID-19, after the massive vaccination campaign that, combined with the new virus variants, has redu5ced the mortality rate of the COVID-19. This is a crucial point.
The issue discussed in the introduction lines 78-96
Moreover, it could be of interest a new paragraph about the effect of the vaccination on the cytokine storm.
These suggestions may improve the novelty degree of the manuscript.
The issue discussed in the introduction lines 397-407 in the discussion
Reviewer 2 Report
The authors addressed the concerns and updated the references
Author Response
We would to thank the reviewer again for his constructive comments.
Round 3
Reviewer 1 Report
The authors have made the requested changes.
This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.
